The present invention is concerned with novel compounds of formula (I) having biocidal properties. The invention further relates to methods for preparing such novel compounds, compositions comprising said novel compounds as well as the use as a biocide for material and plant protection applications.
Micro-organisms are extremely useful, and even indispensable, in processes such as, e.g. alcoholic fermentation, ripening of cheese, baking of bread, production of penicillin, purification of waste water, production of biogas, and the like. However, micro-organisms can also be harmful or highly dangerous; by causing infectious diseases, by forming poisonous or carcinogenic metabolites and by attacking valuable materials, disturbing production processes, or impairment of the quality of products.
Biocides are a broad and diverse group of compounds which are able to kill micro-organisms or inhibit the multiplication of micro-organisms. Biocides can be classified as bactericides, fungicides, algicides, insecticides, acaricides, molluscicides, herbicides and the like. Well-known biocides are, for example, formaldehyde releasing compounds, phenol derivatives, salicylanilides, carbanilides, and quaternary ammonium salts. An extensive overview of biocides is given in xe2x80x9cMicrobiocides for the protection of materialsxe2x80x9d, by Wilfried Paulus, Chapman and Hall, 1st edition, 1993.
An important group of the biocides are the bactericides. Since bacteria occur everywhere, their destructive activity (biodeterioration) is basically unavoidable. Nevertheless materials can be protected with the aid of compounds that prevent the multiplication of bacteria at the relevant sites, either by killing them or inhibiting their development.
The present invention provides for novel compounds of formula (I) unexpectedly having biocidal activity. In particular, said compounds of formula (I) have bactericidal activity.
Structurally related compounds have been described in EP-0,219,756-A1, published on Apr. 29, 1987, having fungicidal activity.
The compounds of the present invention differ from the prior art compounds by the nature of the L moiety.
The present invention concerns compounds of formula (1) 
stereochemically isomeric forms thereof, acid or base addition salts thereof, N-oxides thereof, or quaternary ammonium derivatives thereof,
wherein
the dotted line is an optional bond;
X is a direct bond when the dotted line represents a bond, or
X is hydrogen or hydroxy, when the dotted line does not represent a bond;
R1 and R2 are each independently selected from hydrogen, halo, hydroxy, C1-4alkyl, C1-4alkyloxy, nitro, amino, cyano, trifluoromethyl, trifluoromethoxy, C1-6alkylcarbonyl, hydroxycarbonyl, C1-6alkyloxycarbonyl, aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, aminosulfonyl, di(C1-4alkyl)aminosulfonyl, or xe2x80x94SO3H;
R3 and R4 are each independently selected from hydrogen, halo, hydroxy, C1-4alkyl, C1-4alkyloxy, nitro, amino, cyano, trifluoromethyl, or trifluoromethoxy;
R5 and R6 are each independently selected from hydrogen, halo, hydroxy, C1-4alkyl, C1-4alkyloxy, nitro, amino, cyano, trifluoromethyl, trifluoromethoxy, C1-6alkylcarbonyl, hydroxycarbonyl, C1-6alkyloxycarbonyl, aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, aminosulfonyl, di(C1-4alkyl)aminosulfonyl, or xe2x80x94SO3H;
L is a radical of formula 
xe2x80x83wherein
A1 is a direct bond or C1-6alkanediyl;
A2 is C2-6alkanediyl;
R7 is hydrogen, C1-4alkyl, phenyl or benzyl;
R8 and R9 are each independently hydrogen, C1-6alkyl, aminoC1-6alkyl or mono- or di(C1-4alkyl)aminoC1-6alkyl;
R10 is hydrogen, C1-6alkyl, aminoC1-6alkyl or mono- or di(C1-4alkyl)aminoC1-6alkyl; and
R11 is hydrogen, C1-6alkyl, amino, aminoC1-6alkyl or mono- or di(C1-4alkyl)aminoC1-6alkyl.
As used in the foregoing definitions halo is generic to fluoro, chloro, bromo and iodo; C1-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C1-6alkyl is meant to include C1-4alkyl and the higher homologues thereof having 5 or 6 carbon atoms, such as, for example, 2-methylbutyl, pentyl, hexyl and the like; C1-6alkanediyl defines bivalent straight or branched chain hydrocarbon radicals containing from 1 to 6 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof; C2-6alkanediyl defines bivalent straight or branched chain hydrocarbon radicals containing from 2 to 6 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof.
The term xe2x80x9cstereochemically isomeric formsxe2x80x9d as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E or Z-stereochemistry at said double bond. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.
The invention also comprises the salts which the compounds of formula (1) are able to form with organic or inorganic bases such as amines, alkali metal bases and earth alkaline metal bases, or quaternary ammonium bases, or with organic or inorganic acids, such as mineral acids, sulfonic acids, carboxylic acids or phosphorus containing acids.
Examples of salt-forming mineral acids are hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, chloric acid, perchloric acid or phosphoric acid. Salt-forming sulfonic acids are toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid or trifluoromethane sulfonic acid. Salt-forming carboxylic acids are formic acid, acetic acid, propanoic acid, butanoic acid, and the like. Salt-forming dicarboxylic acids are oxalic acid, malonic acid, succinic acid, glutaric acid, and the like. Salt-forming hydroxy acids are glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, mandelic acid, and the like. Other salt-forming carboxylic acids are trifluoroacetic acid, benzoic acid, chloroacetic acid, phthalic acid, maleic acid, and malonic acid. Phosphorus containing acids are the various phosphonous acids, phosphonic acids and phosphinic acids.
Particular addition salts are acid addition salts obtained by treating the base form of compounds of formula (I) with appropriate acidic biocidal agents such as, e.g. 1,2-benzisothiazolone (BIT), 5-chloro-1,2-benzisothiazolone, 6-chloro-1,2-benzisothiazolone, 5-fluoro- 1,2-benzisothiazolone, 5-methyl-3(2H)-isothiazolone, or 4-bromo-5-methyl-3-isothiazolol. These addition salts can have different stoichiometry such as (1:1), (1:2), (1:3), (2:1), (3:1), (2:3) and so on.
Preferred salt-forming alkali metal hydroxides and earth alkaline metal hydroxides are the hydroxides of lithium, sodium, potassium, magnesium or calcium, most preferably those of sodium or potassium. Examples of suitable salt-forming amines are primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline. Preferred amines are ethylamine, propylamine, diethylamine or triethylamine, with isopropylamine, diethanolamine and 1,4-diazabicyclo[2.2.2]octane being most preferred. Examples of quaternary ammonium bases are, in general, the cations of haloammonium salts, e.g. the tetramethylammonium cation, the trimethylbenzylammonium cation, the triethylbenzylammonium cation, and also the ammonium cation.
The term salt form also comprises metal complexes which the compounds of formula (I) may form. Metal complexes as mentioned above consist of a complex formed between a compound of formula (I) and one or more organic or inorganic metal salt or salts. Examples of said organic or inorganic salts comprise the halogenides, nitrates, sulfates, phosphates, acetates, trifluoroacetates, trichloroacetates, propionates, tartrates, sulfonates, e.g. methylsulfonates, 4-methylphenylsulfonates, salicylates, benzoates and the like of the metals of the second main group of the periodical system, e.g. the magnesium or calcium salts, of the third or fourth main group, e.g. aluminium, tin, lead as well as the first to the eighth transition groups of the periodical system such as, for example, chromium, manganese, iron, cobalt, nickel, copper, zinc and the like. Preferred are the metals pertaining to the transition elements of the fourth period. The metals may be present in each of their possible valences. The metal ions may be present in any of their possible valences, the most preferred metal copper being most advantageously used in its divalent form Cu(II). Suitable copper compounds are copper sulfate, acetate, hydroxide, oxide, borate, fluoride and in particular copper hydroxide carbonate Cu(OH)2CuCO3. The complexes can be mono- or polynuclear, they may contain one or more parts of the organic molecule as ligands.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
A group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply
a) R1 and R2 are each independently selected from hydrogen, halo, or xe2x80x94SO3H;
b) R3 and R4 are hydrogen;
c) R5 and R6 are each independently selected from hydrogen, halo, hydroxy, C1-4alkyl, C1-4alkyloxy or xe2x80x94SO3H;
d) R7 is hydrogen or C1-4alkyl;
e) R8 and R9 are each independently hydrogen, C1-4alkyl, or aminoC1-6alkyl;
f) R10 is hydrogen, C1-6alkyl, or di(C1-4alkyl)aminoC1-6alkyl;
g) R11 is hydrogen, C1-6alkyl, amino, aminoC1-6alkyl or di(C1-4alkyl)aminoC1-6alkyl;
h) A1 is a direct bond or C2-4alkanediyl;
g) A2 is C2-4alkanediyl.
More interesting compounds are those compounds of formula (I) wherein L is a radical of formula (a-1), (a-2), (a-3), (a-5), (a-7), (a-8), or (a-10), wherein R10 is hydrogen, C1-6alkyl, or di(C1-4alkyl)aminoC1-6alkyl.
Other more interesting compounds are those compounds of formula (I) wherein L is a radical of formula (a-3) or (a-9) wherein R11 is hydrogen, C1-6alkyl, amino, (aminoC1-6alkyl or di(C1-4alkyl)aminoC1-6alkyl.
Also more interesting compounds are those compounds of formula (I) wherein L is a radical of formula (a-4) or (a-6) wherein R8 and R9 are each independently hydrogen, C1-4alkyl, or aminoC1-6alkyl.
Particular compounds are those compounds of formula (I) wherein L is a radical of formula (a-1) wherein R10 is hydrogen.
Other particular compounds are those compounds of formula (1) wherein L is a radical of formula (a-4) wherein A2 is C2-4alkanediyl and R8 and R9 are each independently hydrogen or C1-4alkyl.
Further particular compounds are those compounds of formula (I) wherein L is a radical of formula (a-6) wherein A1 and A2 are C2-4alkanediyl, R7 is hydrogen or C1-4alkyl, and R8 and R9 are each independently hydrogen or C1-4alkyl.
Preferred compounds are
4-[[(1,1xe2x80x2-biphenyl)-4-yl]phenylmethyl](1,4xe2x80x2-bipiperidine);
4-[[(1,1xe2x80x2-biphenyl)-4-yl]phenylmethyl]-1-piperidinepropanamine; and
N-[3-[(1,1xe2x80x2-biphenyl)-4-yl]-3-phenylpropyl]-1,3-propanediamine;
and acid or base addition salts, the stereoisomeric forms, the N-oxides, or quaternary ammonium derivatives thereof.
Other preferred compounds are the acid addition salts obtained by treating the base form of compounds of formula (I) with appropriate acidic biocidal agents such as, e.g. 1,2-benzisothiazolone (BIT).
Particular preferred acid addition salts are the BIT salts of
4-[[(1,1xe2x80x2-biphenyl)-4-yl]phenylmethyl](1,4xe2x80x2-bipiperidine),
4-[[(1,1xe2x80x2-biphenyl)-4-yl]phenylmethyl]-1-piperidinepropanamine, and
N-[3-[(1,1xe2x80x2-biphenyl)-4-yl]-3-phenylpropyl]-1,3-propanediamine;
or the BIT salts of a stereoisomeric form, an N-oxide, or a quaternary ammonium derivative of the latter compounds.
Compounds of formula (I-a), defined as compounds of formula (I) wherein X is hydroxy and the dotted line does not represent a bond, can be prepared by reacting an organometallic derivative of an intermediate of formula (II), wherein halo represents chloro, bromo or iodo, with an intermediate of formula (III). Said organometallic derivative of an intermediate of formula (II) can be prepared, for instance, by converting said intermediate (II) into its corresponding Grignard analogue using magnesium in a reaction-inert solvent such as, e.g. diethyl ether or tetrahydrofuran. For those compounds of formula (I-a) wherein the radical L bears a radical of formula R8, R9 or R10 being hydrogen, depending upon the reaction conditions it can be advisable to temporarily protect said R8, R9 or R10 by converting R8, R9 or R10 into an appropriate protecting group such as, e.g. C1-6alkyloxycarbonyl. 
Compounds of formula (I-a) can be converted to compounds of formula (I-b), being compounds of formula (I) wherein X is a direct bond and the dotted line represents a bond, by dehydrating said compounds of formula (I-a) under art-known reaction conditions as exemplified, for instance, in example B.3. 
Compounds of formula (I-b) can be converted to compounds of formula (I-c), being compounds of formula (I) wherein X is hydrogen and the dotted line does not represent a bond, by hydrogenating said compounds of formula (I-a). 
Compounds of formula (I-c-1), defined as compounds of formula (I-c) wherein L1 represents a radical of formula (a-2), (a-3), (a-6) to (a-10) wherein A1 is a direct bond, can be prepared by alkylating an intermediate of formula (V) with an intermediate of formula (IV), wherein W is an appropriate leaving group such as, for example, halo, e.g. fluoro, chloro, bromo, iodo, or in some instances W may also be a sulfonyloxy group, e.g. methanesulfonyloxy, benzenesulfonyloxy, trifluoromethanesulfonyloxy and the like reactive leaving groups. The reaction can be performed in a reaction-inert solvent such as, for example, acetonitrile, and optionally in the presence of a suitable base such as, for example, sodium carbonate, potassium carbonate or triethylamine. For those compounds of formula (I-c-1) wherein the radical L1 bears a radical of formula R8, R9 or R10 being hydrogen, depending upon the reaction conditions it can be advisable to temporarily protect said R8, R9 or R10 by converting R8, R9 or R10 into a suitable protecting group such as, e.g. C1-6alkyloxycarbonyl. 
Compounds of formula (I-d), defined as compounds of formula (I) wherein L2 represents a radical of formula (a-6) to (a-10) wherein A1 is C1-6alkanediyl, can be prepared by N-alkylating an intermediate of formula (VII) with an intermediate of formula (VI), wherein W is a leaving group as defined herein-above. 
Said intermediate of formula (VII) has one of the following structures: 
For those intermediates of formula (VII) wherein the radical of formula R7, R8, R9 or R10 is hydrogen, depending upon the reaction conditions, it can be advisable to temporarily protect said R7, R8, R9 or R10 by converting R7, R8, R9 or R10 into a suitable protecting group such as, e.g. C1-6alkyloxycarbonyl.
Compounds of formula (I-e), defined as compounds of formula (I) wherein L3 represents a radical of formula (a-2) or (a-4) can be prepared by reductively N-alkylating an intermediate of formula (VIII) with an intermediate of formula (IX-1) or (X-1); or by N-alkylating said intermediate of formula (VIII) with an intermediate of formula (IX-2) or (X-2). 
Said intermediate of formula (IX) or (X) has the following structure: 
For those intermediates of formula (IX) or (X) wherein the radical of formula R8, R9 or R10 is hydrogen, depending upon the reaction conditions, it can be advisable to temporarily protect said R8, R9 or R10 by converting R8, R9 or R10 into a suitable protecting group such as, e.g. C1-6alkyloxycarbonyl.
The compounds of formula (I) may also be converted into each other via art-known reactions or functional group transformations. For instance, compounds of formula (I) wherein R10 or R11 are hydrogen can be converted into compounds of formula (I) wherein R10 or R11 is C1-6alkyl using art-known N-alkylation procedures.
Intermediates of formula (IV) can be prepared as described in working example A.7, intermediates of formula (VI) can be prepared as described in working examples A.5 and A.6, and intermediates of formula (VIII) can be prepared as described in working examples A.2 and A.3.
The starting materials and some of the intermediates are known compounds and are commercially available or may be prepared according to conventional reaction procedures generally known in the art.
The compounds of formula (I) as prepared in the hereinabove described processes may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The biocidal properties of the compounds of formula (I) are exemplified in the biological section C herein-below, In particular, the compounds of formula (I) have bactericidal properties as evidenced in examples C. 1 and C.2.
Furthermore, the compounds of formula (I) were also found to be active against certain yeasts, as evidenced in example C.3.
A number of compounds of formula (I) also have algicidal properties.
The compounds of the present invention are active against a broad range of bacteria, both gram-positive as gram-negative bacteria. As examples of such gram-positive bacteria there may be named Micrococcus flavus, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus faecalis, and the like. As example of such gram-negative bacteria there may be named Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas stutzeri, Pseudomonas cepacia, Pseudomonas fluorescens, Pseudomonas sp., Proteus vulgaris, Proteus morganii, Eschericia coli, Klebsiella aerogenes, Enterobacter cloacae, Salmonella typhimurium, Serratia marcescens, and the like. Experience has shown that gram-negative bacteria (which are additionally protected by an outer membrane compared to gram-positive bacteria), especially Pseudomonades, are more resistant than gram-positive bacteria against biocides (xe2x80x9cMicrobiocides for the protection of materialsxe2x80x9d, by Wilfried Paulus, Chapman and Hall, 1st edition, 1993). Therefore, compounds having bactericidal properties against gram-negative bacteria, especially against Pseudomonades, are highly desirous.
The compounds of formula (I) can be used in a variety of applications
industrial aqueous process fluids, e.g. cooling waters, pulp and papermill process waters and suspensions, secondary oil recovery systems, spinning fluids, metal working fluids, and the like
in-tank/in-can protection of aqueous functional fluids, e.g. polymer emulsions, water based paints and adhesives, glues, starch slurries, thickener solutions, gelatine, wax emulsions, inks, polishes, pigment and mineral slurries, rubber latexes, concrete additives, drilling muds, toiletries, aqueous cosmetic formulations, pharmaceutical formulations, and the like
antimicrobial treatment of materails that finally contain little or no water in a free state, e.g. paints and adhesive films, textiles, paper, paperboards, plastics, hoses, cords, rubber product, leather, wood, timber materials, and the like
disinfection of inanimate surfaces (e.g. in hospitals, households, animal stables, the food industry) and equipment.
The compounds of formula (I) can be used for the protection of plants and plant-derived materials from degradation by phytopathogenic bacteria. As examples of such phytopathogenic bacteria there may be named Xanthomonas campestris pv. phaseoli, Pseudomonas syringae pv. phaseolicola, Erwinia amylovora, Agrobacterium tumefaciens, Clavibacter michiganense, Erwinia carotovora, Erwinia tracheiphila, Pseudomonas pisi, Pseudomonas solanacearum, Streptomyces scabies, Xylella fastidiosa, and the like. Hence, the compounds of formula (I) possess advantageous curative, preventive and systemic biocidal activity to protect plants, in particular culture plants. Said compounds of formula (I) can be used to protect plants or parts of plants, e.g. fruits, blossoms, flowers, foliage, stems, roots, tubers of plants or culture plants infected, harmed or destroyed by micro-organisms, whereby later-growing parts of plants are protected against such micro-organisms.
The compounds of formula (I) can further be used in seed disinfection (fruits, tubers, cereal grains) and to treat plant cuttings as well as to combat phytopathogenous microorganims occurring in the soil.
As examples of the wide variety of culture plants in which the compounds of the present invention can be used, there may be named for example cereals, e.g. wheat, barley, rye, oats, rice, sorghum and the like; beets, e.g. sugar beet and fodder beet; pome and stone fruits and berries, e.g. apples, pears, plums, peaches, almonds, cherries, strawberries, raspberries and blackberries; leguminous plants, e.g. beans, lentils, peas, soy beans; oleaginous plants, e.g. rape, mustard, poppy, olive, sunflower, coconut, castor-oil plant, cocoa, ground-nuts; cucurbitaceae, e.g. pumpkins, gherkins, melons, cucumbers, squashes; fibrous plants, e.g. cotton, flax, hemp, jute; citrus fruits, e.g. orange, lemon, grapefruit, mandarin; vegetables, e.g. spinach, lettuce, asparagus, brassicaceae such as cabbages and turnips, carrots, onions, tomatoes, potatoes, hot and sweet peppers; laurel-like plants, e.g. avocado, cinnamon, camphor tree; or plants such as maize, tobacco, nuts, coffee, sugar-cane, tea, vines, hops, bananas, rubber plants, as well as ornamental plants, e.g. flowers, shrubs, deciduous trees and evergreen trees such as conifers. This enumeration of culture plants is given with the purpose of illustrating the invention and not to delimiting it thereto.
The compounds of formula (I) and compositions comprising one or more of these compounds can also be used to prevent the formation of biofilms. Biofilms are composed of millions of microorganisms (bacteria, fungi, algae, and protozoa) that accumulate on surfaces in aqueous environments (Science, vol. 273, p. 1795-1797, 1996). These film-forming microbes excrete a glue-like substance that anchors them to materials such as metals, plastics, tissue, and soil particles. Once anchored to a surface, biofilm microorganisms carry out a variety of detrimental or beneficial reactions, depending on the surrounding conditions. Some of the problems associated with biofilm formation include biofouling (fouling or contamination linked to microbial activity), biocorrosion (especially of industrial pipes), oil field souring (the reduction of sulfates by microbes in soil) and infections caused by biofilm growing on host tissues or medical implants. Biofilm-related problems cost industry billions of dollars annually by corroding pipes, reducing heat transfer or hydraulic pressure in industrial cooling systems, plugging water injection jets, and clogging water filters. In addition, biofilms cause major medical problems through infecting host tissues, harboring bacteria that contaminate drinking water, causing rejection of medical implants, and contamination of medical devices ranging from contact lenses, urinary catheters to artificial hearts.
The compounds of formula (I) are stable compounds and no precautionary measures are required for handling them.
In view of the biological activity of the compounds of formula (I) as demonstrated in examples C.1 to C.4, the subject compounds are useful for controlling, i.e. preventing, inhibiting, eliminating, combatting, or eradicating, micro-organisms.
The invention also relates to biocidal compositions containing one or more inert carriers and, if desired, other adjuvants and as active ingredient a biocidally effective amount of a compound of formula (I) as defined hereinabove. Further the invention relates to a method of controlling micro-organisms, in particular bacteria, by the application of the novel compounds to said micro-organisms.
In the method for controling micro-organisms according to the invention the compounds of formula (I) are used in unmodified form or, preferably, together with the adjuvants conventionally employed in the art of formulation. They are therefore formulated following art-known procedures to emulsifiable concentrates, directly sprayable or dilutable solutions, dilute emulsions, wettable powders, soluble powders, dusts, granulates, and also encapsulations in e.g. polymer substances. Depending on the nature of the compositions, the methods of application, such as spraying, atomising, dusting, scattering or pouring, are chosen in accordance with the intended objectives and the prevailing circumstances.
The formulations, i.e. the compositions, preparations or mixtures containing the compound (active ingredient) of formula (I) and, where appropriate, a solid or liquid adjuvant, are prepared in known manner, e.g. by homogeneously mixing and/or grinding the active ingredients with extenders, e.g. solvents, solid carriers and, where appropriate, surface-active compounds (surfactants).
Suitable solvents are aromatic hydrocarbons, preferably the fractions containing 8 to 12 carbon atoms, such as, alkylbenzene mixtures, e.g. dimethylbenzene mixtures or alkylated naphthalenes, aliphatic or alicyclic hydrocarbons such as paraffins, cyclohexane or tetrahydronaphtalene, alcohols such as ethanol, propanol or butanol, glycols and their ethers and esters, such as propylene glycol or dipropylene glycol ether, ketones such as cyclohexanone, isophorone or diacetone alcohol, strongly polar solvents such as N-methyl-2-pyrrolidone, dimethylsulfoxide or water, vegetable oils and their esters, such as rape, castor or soybean oil, possibly also silicon oil.
The solid carriers used e.g. for dusts and dispersible powders are normally natural mineral fillers such as calcite, talcum, kaolin, montmorillonite or attapulgite. In order to improve the physical properties it is also possible to add highly dispersed silicic acid or highly dispersed absorbent polymers. Suitable granulated adsorptive carriers are porous types, for example pumice, broken brick, sepiolite or bentonite; and suitable nonsorbent carriers are materials such as calcite or sand. In addition, a great number of pregranulated materials of inorganic or organic nature can be used, e.g. especially dolomite or pulverised plant residues.
Depending on the nature of the compound of formula (I) to be formulated, suitable surface-active compounds are non-ionic, cationic and/or anionic surfactants having good emulsifying, dispersing and wetting properties. The term xe2x80x9csurfactantsxe2x80x9d will also be understood as comprising mixtures of surfactants.
Suitable anionic surfactants can be both water-soluble soaps and water-soluble synthetic surface-active compounds.
Suitable soaps are the alkali metal salts, earth alkaline metal salts or unsubstituted or substituted ammonium salts of higher fatty acids (C10-C22), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures which can be obtained e.g. from coconut oil or tallow oil. In addition, there may also be mentioned fatty acid methyltaurin salts.
More frequently, however, so-called synthetic surfactants are used, especially fatty sulfonates, fatty sulfates, sulfonated benzimidazole derivatives or alkylarylsulfonates.
The fatty sulfonates or sulfates are usually in the form of alkali metal salts, earth alkaline metal salts or unsubstitued or substituted ammonium salts and contain a C8-22alkyl radical which also includes the alkyl moiety of acyl radicals, e.g. the sodium or calcium salt of lignosulfonic acid, of dodecylsulfate or of a mixture of fatty alcohol sulfates obtained from natural fatty acids. These compounds also comprise the salts of sulfuric acid esters and sulfonic acids of fatty alcohol/ethylene oxide adducts. The sulfonated benzimidazole derivatives preferably contain 2 sulfonic acid groups and one fatty acid radical containing 8 to 22 carbon atoms. Examples of alkylarylsulfonates are the sodium, calcium or triethanolamine salts of dodecylbenzene sulfonic acid, dibutylnaphthalenesulfonic acid, or of a naphthalenesulfonic acid/formaldehyde condensation product. Also suitable are corresponding phosphates, e.g. salts of the phosphoric acid ester of an adduct of p-nonylphenol with 4 to 14 moles of ethylene oxide, or phospholipids.
Non-ionic surfactants are preferably polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, or saturated or unsaturated fatty acids and alkylphenols, said derivatives containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenols.
Further suitable non-ionic surfactants are the water-soluble adducts of polyethylene oxide with polypropylene glycol, ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethylene glycol ether groups and 10 to 100 propylene glycol ether groups. These compounds usually contain 1 to 5 ethylene glycol units per propylene glycol unit.
Representative examples of non-ionic surfactants are nonylphenolpolyethoxyethanols, castor oil polyglycol ethers, polypropylene/polyethylene oxide adducts, tributyl-phenoxypolyethoxyethanol, polyethylene glycol and octylphenoxypolyethoxyethanol.
Fatty acid esters of polyethylene sorbitan, such as polyoxyethylene sorbitan trioleate, are also suitable non-ionic surfactants.
Cationic surfactants are preferably quaternary ammonium salts which contain, as N-substituent, at least one C8-C22alkyl radical and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl or hydroxy-lower alkyl radicals. The salts are preferably in the form of halides, methylsulfates or ethylsulfates, e.g. stearyl-trimethylammonium chloride or benzyldi(2-chloroethyl)ethylammonium bromide.
The surfactants customarily employed in the art of formulation are described e.g. in the following publications:
xe2x80x9cMcCutcheon""s Detergents and Emulsifiers Annualxe2x80x9d, MC Publishing Corp., Ridgewood, N.J., 1981; H. Stache, xe2x80x9cTensid-Taschenbuchxe2x80x9d, 2nd Edition, C. Hanser Verlag, Munich and Vienna, 1981, M. and J. Ash, xe2x80x9cEncyclopedia of Surfactantsxe2x80x9d, Vol. I-III, Chemical Publishing Co., New York, 1980-81.
Compositions comprising a compound of formula (I) may further comprise other active ingredients, e.g. other biocides, in particular fungicides, bactericides, acaricides, nematicides, insecticides or herbicides, for example so as to widen the spectrum of action or to prevent the build up of resistance. In many cases, this results in synergistic effects, i.e. the activity of the mixture exceeds the activity of the individual components.
As biocidal agents, which may be used in combination with the compounds of the present invention there may be considered products of the following classes:
Fungicides
2-aminobutane; 2-anilino-4-methyl-6-cyclopropyl-pyrimidine; 2xe2x80x2,6xe2x80x2-dibromo-2-methyl-4xe2x80x2-trifluoromethoxy-4xe2x80x2-trifluoro-methyl-1,3-thiazole-5-carboxanilide; 2,6-di-chloro-N-(4-trifluoromethylbenzyl)benzamide; (E)-2-methoxyimino-N -methyl-2-(2-phenoxyphenyl)-acetamide; 8-hydroxyquinoline sulphate; methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy]-phenyl}-3-methoxyacrylate; methyl (E)-methoximino[alpha-(o-tolyloxy)-o-tolyl]acetate; 2-phenylphenol (OPP), aldimorph, ampropylfos, anilazine, azaconazole, benalaxyl, benodanil, benomyl, binapacryl, biphenyl, bitertanol, blasticidin-S, bromuconazole, bupirimate, buthiobate, calcium polysulphide, captafol, captan, carbendazim, carboxin, quinomethionate, chloroneb, chloropicrin, chlorothalonil, chlozolinate, cufraneb, cymoxanil, cyproconazole, cyprofuram, dichlorophen, diclobutrazol, diclofluanid, diclomezin, dicloran, diethofencarb, difenoconazole, dimethirimol, dimethomorph, diniconazole, dinocap, diphenylamine, dipyrithion, ditalimfos, dithianon, dodine, drazoxolon, edifenphos, epoxyconazole, ethirimol, etridiazole, fenarimol, fenbuconazole, fenfuram, fenitropan, fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, fluoromide, fluquinconazole, flusilazole, flusulfamide, flutolanil, flutriafol, folpet, fosetyl-aluminium, fthalide, fuberidazole, furalaxyl, furmecyclox, guazatine, hexachlorobenzene, hexaconazole, hymexazol, imazalil, imibenconazole, iminoctadine, iprobenfos (IBP), iprodione, isoprothiolane, kasugamycin, copper preparations such as: copper hydroxide, copper naphthenate, copper oxychloride, copper sulphate, copper oxide, oxine-copper and Bordeaux mixture, mancopper, mancozeb, maneb, mepanipyrim, mepronil, metalaxyl, metconazole, methasulfocarb, methfuroxam, metiram, metsulfovax, myclobutanil, nickel dimethyldithiocarbamate, nitrothal-isopropyl, nuarimol, ofurace, oxadixyl, oxamocarb, oxycarboxin, pefurazoate, penconazole, pencycuron, phosdiphen, pimaricin, piperalin, polyoxin, probenazole, prochloraz, procymidone, propamocarb, propiconazole, propineb, pyrazophos, pyrifenox, pyrimethanil, pyroquilon, quintozene (PCNB), sulphur and sulphur preparations, tebuconazole, tecloftalam, tecnazene, tetraconazole, thiabendazole, thicyofen, thiophanate-methyl, thiram, tolclophos-methyl, tolylfluanid, triadimefon, triadimenol, triazoxide, trichlamide, tricyclazole, tridemorph, triflumizole, triforine, triticonazole, validamycin A, vinclozolin, zineb, ziram. Particular fungicides are thiabendazole; isothia- and benzisothiazolone derivatives such as, e.g. 1,2-benzisothiazolone (BIT); oxathiazines such as bethoxazin (i.e. 3-(benzo[b]thien-2-yl)-5,6-dihydro-1,4,2-oxathiazine, 4-oxide); and fungicidally active triazoles such as, for example, azaconazole, bromuconazole, cyproconazole, difenoconazole, epoxiconazole, fenbuconazole, hexaconazole, metconazole, penconazole, propiconazole, tebuconazole, or triticonazole.
Bactericides
bronopol, dichlorophen, nitrapyrin, nickel dimethyldithiocarbamate, kasugamycin, octhilinone, furanecarboxylic acid, oxytetracyclin, probenazole, streptomycin, tecloftalam, copper sulphate and other copper preparations.
Insecticides/Acaricides/Nematicide
abamectin, AC 303 630, acephate, acrinathrin, alanycarb, aldicarb, alphamethrin, amitraz, avermectin, AZ 60541, azadirachtin, azinphos A, azinphos M, azocyclotin, Bacillus thuringiensis, bendiocarb, benfuracarb, bensultap, beta-cyfluthrin, bifenthrin, BPMC, brofenprox, bromophos A, bufencarb, buprofezin, butocarboxin, butylpyridaben, cadusafos, carbaryl, carbofuran, carbophenothion, carbosulfan, cartap, CGA 157 419, CGA 184699, chloethocarb, chlorethoxyfos chlorfenvinphos, chlorfluazuron, chliormephos, chlorpyrifos, chlorpyrifos M, cis-resmethrin, clocythrin, clofentezine, cyanophos, cycloprothrin, cyfluthrin, cyhalothrin, cyhexatin, cypermethrin, cyromazine, deltamethrin, demeton-M, demeton-S, demeton-S-methyl, diafenthiuron, diazinon, dichlofenthion, dichlorvos, dicliphos, dicrotophos, diethion, diflubenzuron, dimethoate, dimethylvinphos, dioxathion, disulfoton, edifenphos, emamectin, esfenvalerate, ethiofencarb, ethion, ethofenprox, ethoprophos, etrimphos, fenamiphos, fenazaquin, fenbutatin oxide, fenitrothion, fenobucarb, fenothiocarb, fenoxycarb, fenpropathrin, fenpyrad, fenpyroximate, fenthion, fenvalerate, fipronil, fluazinam, flucycloxuron, flucythrinate, flufenoxuron, flufenprox, fluvalinate, fonophos, formothion, fosthiazate, fubfenprox, furathiocarb, HCH, heptenophos, hexaflumuron, hexythiazox, imidacloprid, iprobenfos, isazophos, isofenphos, isoprocarb, isoxathion, ivemectin, lambda-cyhalothrin, lufenuron, malathion, mecarbam, mervinphos, mesulfenphos, metaldehyde, methacrifos, methamidophos, methidathion, methiocarb, methomyl, metolcarb, milbemectin, monocrotophos, moxidectin, naled, NC 184, NI 25, nitenpyram, omethoate, oxamyl, oxydemethon M, oxydeprofos, parathion A, parathion M, permethrin, phenthoate, phorate, phosalone, phosmet, phosphamdon, phoxim, pirimicarb, pirimiphos M, pirimiphos A, profenofos, promecarb, propaphos, propoxur, prothiofos, prothoate, pymetrozin, pyrachlophos, pyridaphenthion, pyresmethrin, pyrethrum, pyridaben, pyrimidifen, pyriproxifen, quinalphos, RH 5992, salithion, sebufos, silafluofen, sulfotep, sulprofos, tebufenozid, tebufenpyrad, tebupirimiphos, teflubenzuron, tefluthrin, temephos, terbam, terbufos, tetrachlorvinphos, thiafenox, thiodicarb, thiofanox, thiomethon, thionazin, thuringiensin, tralomethrin, triarathen, triazophos, triazuron, trichlorfon, triflumuron, trimethacarb, vamidothion, XMC, xylylcarb, zetamethrin.
Other biocidal agents that may be used in combination with the compounds of the present invention there may be considered products of the following classes: phenol derivatives such as 3,5-dichlorophenol, 2,5-dichlorophenol, 3,5-dibromophenol, 2,5-dibromophenol, 2,5-(resp. 3,5)-dichloro-4-bromophenol, 3,4,5-trichlorophenol, chlorinated hydrodiphenylethers such as, for example, 2-hydroxy-3,2xe2x80x24xe2x80x2-trichloro-diphenylether, phenylphenol, 4-chloro-2-phenylphenol, 4-chloro-2-benzylphenol, dichlorophene, hexachlorophene; aldehydes such as formaldehyde, glutaraldehyde, salicylaldehyde; alcohols such as phenoxyethanol; antimicrobially active carboxylic acids and their derivatives; organometallic compounds such as tributyltin compounds; iodine compounds such as iodophores, iodonium compounds; mono-, di- and polyamines such as dodecylamine or 1,10-di(n-heptyl)-1,10-diaminodecane; sulfonium- and phosphonium compounds; mercapto compounds as well as their alkali, earth alkaline and heavy metal salts such as 2-mercaptopyridine-N-oxide and its sodium and zinc salt, 3-mercaptopyridazin-2-oxide, 2-mercaptoquinoxaline-1-oxide, 2-mercaptoquinoxaline-di-N-oxide, as well as the symmetrical disulfides of said mercapto compounds; ureas such as tribromo- or trichlorocarbanilide, dichlorotrifluoromethyl-diphenylurea; tribromosalicylanilide; 2-bromo-2-nitro-1,3-dihydroxypropane; dichlorobenzoxazolon; and chlorohexidine.
The biocidal compositions which are preferably employed in the method of the invention usually contain 0.1 to 99%, preferably 0.1 to 95% of a compound of formula (I), 1 to 99% of a solid or liquid adjuvant, and 0 to 25% preferably 0.1 to 25% of a surfactant. The commercial forms of said biocidal compositions are advantageously concentrates which can easily be diluted by the end user.
The compositions can also contain further additives, such as, stabilizers, e.g. optionally epoxidized vegetable oils (epoxidized coconut, rape or soybean oil), defoamers, e.g. silicon oil, conservatives, viscosity regulators, binding materials, fillers and dung or other materials for special purposes.
The present invention also relates to compositions comprising a compound of formula (I) and another active ingredient, as enumerated hereabove, in quantities producing a synergistic effect, and a carrier. In particular, synergistic compositions of a compound of formula (I) with another bacteride and/or another fungicide are envisaged.
Preferred formulations are composed in particular of the following constituents (%=percentage by weight):
Emulsifiable Concentrates
active ingredient: 1 to 9%, preferably 2 to 5%
surfactant: 5 to 30% preferably 10 to 20%
liquid carrier: 5 to 94% preferably 70 to 85%
Dusts
active ingredient: 0.1 to 10%, preferably 0.1 to 1%
solid carrier: 99.9 to 90%, preferably 99.9 to 99%
Suspension Concentrates
active ingredient: 5 to 75%, preferably 10 to 50%
water: 94 to 24%, preferably 88 to 30%
surfactant: 1 to 40%, preferably 2 to 30%
Wettable Powders
active ingredient: 0.5 to 90%, preferably 1 to 80%
surfactant: 0.5 to 20%, preferably 1 to 15%
solid carrier: 5 to 95%, preferably 15 to 90%
Granulates
active ingredient: 0.5 to 30%, preferably 3 to 15%
solid carrier: 99.5 to 70%, preferably 97 to 85%
The following examples are intended to illustrate the present invention.
Experimental Part
In the procedures described hereinafter the following abbreviations were used: xe2x80x9cACNxe2x80x9d stands for acetonitrile; xe2x80x9cTHFxe2x80x9d, which stands for tetrahydrofuran; xe2x80x9cDCMxe2x80x9d stands for dichloromethane; xe2x80x9cDIPExe2x80x9d stands for diisopropylether; xe2x80x9cEtOAcxe2x80x9d stands for ethyl acetate; xe2x80x9cNH4OAcxe2x80x9d stands for ammonium acetate; xe2x80x9cHOAcxe2x80x9d stands for acetic acid; xe2x80x9cMIKxe2x80x9d stands for methyl isobutyl ketone.
For some chemicals the chemical formula was used, e.g. NaOH for sodium hydroxide, K2CO3 for potassium carbonate, H2 for hydrogen gas, MgSO4 for magnesium sulfate, CuO.Cr2O3 for copper chromite, N2 for nitrogen gas, CH2Cl2 for dichloromethane, CH3OH for methanol, NH3 for ammonia, HCl for hydrochloric acid, NaH for sodium hydride, CaCO3 for calcium carbonate, CO for carbon monoxide, and KOH for potassium hydroxide.
Of some compounds of formula (I) the absolute stereochemical configuration was not experimentally determined. In those cases the stereochemically isomeric form which was first isolated is designated as xe2x80x9cAxe2x80x9d and the second as xe2x80x9cBxe2x80x9d, without further reference to the actual stereochemical configuration.